Friday Feature: Watching the immune system work

I can’t resist it — another movie. This one is from Ralph Weissleder‘s lab, and it’s a doozy. We are looking inside the spleen of a live mouse, and we are watching a monocyte (blue track) sitting peacefully in the spleen wake up in response to an injury and get out into the blood to help heal the wound.

I know not everyone adores immunology, but I do. Where else do you get such frequent, visible cell fate decisions, and so many hugely consequential checks and balances? It’s a systems biologist’s playground. (Those who feel that their own corner of biology is even better, feel free to comment. Neurobiology, anyone?)

Anyway, so — what is a monocyte? It’s a white blood cell subtype that has some fairly important functions of its own, and can also differentiate into macrophages (the famous “big eaters”) and dendritic cells (so called because they have long “dendrite-like” projections — like neurons — that allow them to touch and communicate with many cells at once). All three cell types eat debris and foreign bodies, and they can all act as alarm bells for the rest of the immune system if what they eat turns out to be scary stuff. Until the publication of this paper, however, we thought that there was one very fundamental difference between these cell types. Monocytes (it was believed) circulate in the blood and rush to the site of injury; they clear dead tissue away and secrete cytokines that lead to inflammation (mostly a good thing and helpful to healing, but very bad if uncontrolled). In contrast, macrophages and dendritic cells embed themselves in tissues and wait for the infection to come to them.

Not so. The suspicions of Swirski et al. were aroused when they realized that after a heart attack (myocardial infarction) the number of monocytes that rush to the site of injury is larger than the total number of monocytes available in the blood. So they looked for tissues that might serve as monocyte reservoirs, and found a surprising number of monocytes in the spleen.

Are these spleen-resident cells really monocytes, and are they really functional? You have to ask these questions if the conventional wisdom is that the cell types you are studying simply don’t exist at this location. The characterization of the monocytes shows that they have all the right surface marker proteins and morphological characteristics, and none of the wrong ones. But can they be activated to leave their safe haven and respond to injury, or are they basically retired?

The video above is one significant piece of evidence that these spleen-resident cells really do act as a reservoir to supply needed monocytes to areas that have been wounded. When a signal saying “I have been damaged” is circulating — in this case angiotensin II, which looks as if it may be a major signal after a heart attack — the monocytes in the spleen start moving around, bump into blood vessels, get out into the circulation, and home in on the site of injury. It’s not the only piece of evidence — you can, for example, remove the spleen from a mouse and replace it with a spleen that has marked monocytes, then look at where the monocytes (which you now know are only the monocytes that started from the spleen) end up. All the lines of data come to the same conclusion: spleen-resident monocytes exist, even though they have been missed for the last 50 years or so, and they are a significant source (over 40%!) of the monocytes that attempt to repair wounds and other major damage. This opens up a new line of inquiry about how monocytes decide to circulate or reside in the spleen, what calls to action they recognize, and how (in the cases where they overdo the response) we could persuade them to dampen their enthusiasm a bit. And, why bother with the splenic reservoir — why aren’t all the monocytes circulating? Any ideas?